RAS SIGNAL TRANSDUCTION IN CELL CYCLE RESPONSE TO RADIATION

细胞周期辐射反应中的 RAS 信号转导

• 批准号: 6300567
• 负责人: WILLIAM G. MCKENNA
• 金额: $ 18.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-17 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300567
• 关键词: DNA damage; animal tissue; apoptosis; biological signal transduction; cell cycle; cell cycle proteins; cyclins; enzyme inhibitors; gene expression; gene induction /repression; gene interaction; gene mutation; genetic regulation; human tissue; microinjections; mitogen activated protein kinase; oncogenes; phenotype; phosphoprotein phosphatase; protein kinase; protein structure function; radiation genetics; radiation resistance; radiation sensitivity; synchronous cell division; transfection /expression vector

Radio-resistance is a major cause of treatment failure in patients with overwise localized, curable malignancies. Ras transfection of rodent cells offers a useful model system to study aspects of the radio-resistant phenotype since it allows the reliable creation of radio-resistant cells on a uniform genetic background. This system permits experiments to determine how signal transduction through the ras oncogene is affecting radio-sensitivity by altering the cell cycle response of transferred cells to radiation causing a prolongation of the radiation induced G2 delay. This application will examine three aspects of the ras associated phenotype. It will examine the relationship of radio-resistance and the G2 delay to ras expression. We will block ras action and determine the effect on radiation survival and cell cycle perturbations. It will begin to dissect which of the ras signal transduction pathways is involved in the induction of radio-resistance. We will utilize ras effector domain mutants, mutant members of signal transduction pathways which interact with ras and inhibitors of signal transduction components to identify the key signal transduction elements which are necessary for expression of the ras associated phenotypes. Finally, we will examine how ra expression effects known effectors of the G2 transition, including cyclin B, cdc2 and cdc25C. These studies should enable us to develop a mechanistic model for the induction of radiation resistance by activated oncogene expression. In addition, portions of these aims rely on interactions with other members of the group to specifically address the role of KILLER/DR5 and ATM in radio-resistance.

放射抗药性是患者治疗失败的主要原因 过度局部的、可治愈的恶性肿瘤。啮齿动物细胞的Ras转染 提供了一个有用的模型系统来研究抗辐射的各个方面 表型，因为它可以可靠地创建抗辐射细胞 具有统一的遗传背景。该系统允许实验 确定 ras 癌基因的信号转导如何影响 通过改变转移细胞的细胞周期反应来提高放射敏感性 辐射导致辐射引起的 G2 延迟延长。 该应用程序将检查 ras 相关的三个方面 表型。它将检查辐射抗性和 G2 的关系 ras 表达延迟。我们将阻止ras行动并确定效果 辐射存活和细胞周期扰动。它将开始 剖析哪些 ras 信号转导途径参与 诱导辐射抗性。我们将利用 ras 效应域 突变体，相互作用的信号转导途径的突变体成员 与 ras 和信号转导成分抑制剂一起识别 表达所必需的关键信号转导元件 ras相关表型。最后，我们将研究 ra 的表达方式 影响 G2 转变的已知效应物，包括细胞周期蛋白 B、cdc2 和 CDC25C。这些研究应该使我们能够开发一个机制模型 通过激活癌基因表达诱导辐射抗性。在 此外，这些目标的一部分依赖于与其他成员的互动 该小组专门讨论了 KILLER/DR5 和 ATM 在 抗辐射性。